Macrophages are among the most versatile cells in the body, and their ability to read and respond to their environment is central to, among others, how infections establish; how tumors evade adaptive immunity; and how tissues repair, or fail to do so. Metabolic reprogramming is emerging as a central determinant of this plasticity. Unraveling the metabolic reprogramming behind macrophage plasticity will generate a vast amount of knowledge on disease progression and open novel therapeutic opportunities, but their dynamic nature and remarkable population diversity require study in their intact environmental contexts.
Video 1. Timelapse showing autophagy dynamics in macrophages during fungal infection. From Forn-Cuní et al., Autophagy, 2024. DOI: 10.1080/15548627.2022.2090727
In my previous research, I have shown how lipid dysregulation impairs acute inflammatory responses in immune-infiltrated tissues; how pathogenic autophagy downregulation impairs macrophage function enabling establishment of fungal infection; how glycolytic byproducts from uveal melanoma polarize macrophages to drive angiogenesis and metastasis; or how myelin recycling reconfigures them to promote glioblastoma growth through lipid metabolism. In all these cases, altered metabolism is not a consequence, but a determinant for macrophage response as a pathogenic driver in the ecosystem of the disease. This is consistent with a growing body of evidence demonstrating that metabolites (e.g., succinate, itaconate, lipid-derived signals) are not passive correlates of macrophage function, but active regulators of transcriptional and epigenetic programs. Most mechanisms through which these metabolic states are acquired and their effect in the evolution of disease, however, remain largely unknown.
One reason for this knowledge gap is that macrophage metabolic interactions cannot be uncoupled from both its ontogeny and its microenvironment. For example, it has recently been shown how itaconate has opposite polarization effects in tissue-resident macrophages than in bone marrow derived macrophages depending on their activation context. Yet most studies have been conducted in vitro, where the complex metabolic interplay between macrophages and other cells within the tissue microenvironment is lost; or in animal models that involve tissue analysis at a single end timepoint, relying on a posteriori pseudotime approaches to infer behavioral dynamics rather than directly observing them.
My central hypothesis is that understanding macrophage metabolic reprogramming within its intact tissue environment will reveal metabolic nodes that are therapeutically relevant. This matters most in contexts where macrophages dictate disease outcome and current therapies have failed, such as in life-threatening infections affecting the increasing immunosuppressed population, or in tumors that are refractory to immune checkpoint blockade. In those situations, harnessing macrophage metabolic reprogramming represents an extraordinary therapeutic opportunity.
To address this, I have complemented my research by developing and validating zebrafish models that allow longitudinal, real-time visualization and quantification of macrophage behavior within a whole living disease context, including models for mycobacterial and fungal infections, and orthotopic and metastatic (patient-derived) cancer xenografts. For example, I used these models to mechanistically show how decoupling lipid macrophage metabolism inhibits glioblastoma growth, or how stimulating autophagic flux in macrophages increases survival to invasive aspergillosis by 20%, in the absence of adaptive immunity or antibiotics.
Videos 2–3. Macrophages (magenta) phagocytosing TME-derived injected myelin (yellow) to become lipid-laden macrophages, imaged in live zebrafish embryos starting 2h (left) and 24h post-injection (right). Forn-Cuní, unpublished, 2025.